A potential role of EGFR-inhibitors for the prevention of BRCA1-related breast cancer.

Abstract

#1110 Background: The majority of women who develop a BRCA1-related breast cancer develop an ER-/PR-/HER2- breast cancer. Endocrine prophylaxis does not prevent these ER- breast cancers. Therefore, there is a need to develop novel chemoprevention agents in this population. 67% of BRCA1-associated ER- breast cancers also overexpress epidermal growth factor receptor (EGFR). We therefore examined EGFR as a potential target for chemoprevention
 Methods: We isolated primary mammary epithelial cells (HMECs) from women with a germline BRCA1 mutation who underwent prophylactic mastectomies and from age-matched controls without a mutation who underwent reduction mammoplasties. We used a three-dimensional matrigel-based colony formation assay to assess clonality and proliferative capacity of these cells as well as their response to EGFR-inhibition. Flow cytometry was used to determine the number of EGF binding sites per cell. As a corresponding mouse model we used conditional MMTV-Cre BRCA1-/-p53+/- mice. Results: HMECs from BRCA1 mutation carriers and from controls express EGFR to a similar extent as HCC1937 BRCA1-associated triple-negative breast cancer cells (5x103 binding sites/cell). In ex vivo 3D-cultures we observed that HMECs derived from BRCA1 mutation carriers showed greater clonal and proliferative capacity when compared to normal controls. However while the HMECs derived from BRCA1 mutation carriers and normal controls were equally sensitive to the growth-inhibitory effect of Erlotinib at concentrations as low as 0.2 μM, the ID50 for HCC1937 breast cancer cells was > 10 μM. Similar findings were observed in murine MECs derived from normal control mice as well as BRCA1-/-p53+/- mice which develop breast cancer at the age of 7 to 8 months. Both groups of murine MECs were equally sensitive to Erlotinib growth inhibition. Conclusion: MECs derived from breast tissue of women and mice with a germline BRCA1 mutation express EGFR and are highly sensitive to growth inhibition with the EGFR inhibitor Erlotinib. In contrast, BRCA1-associated HCC 1937 breast cancer cells are more resistant to Erlotinib inhibition despite EGFR expression. We are now studying whether Erlotinib given via oral gavage daily has the potential to delay or prevent breast cancer in this mouse model of BRCA1-related breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1110.